tbuckley/cabot-search huggingface dataset:
Abstract CT543: 18F-FDG PET/CT detects potentially malignant bone metastases in patients with suspected lesions: A prospective clinical trial
Authors: Hui Zhao, Yujie Chang, Zhiyuan Jiang, Zhiyu Wang, Shunyi Ruan
Journal: Cancer Research (2022)

Abstract Tumor metastasis to the skeleton affects over 70% cancer patients, more than any other site of metastasis Skeletal related events (SREs) included spinal cord compression, fracture, bone radiation or surgery, and tumor-related hypercalcemia are severe complications of bone metastases, which impair patients life quality and require particular treatments The gold standard for the definitive diagnosis is still pathological examination, which needs pre-biopsy imaging review to improve the diagnosis efficacy Classic imaging review method for being CT (Computed Tomography) and 18F-FDG PET/CT Research has shown that 18F-FDG PET/CT is superior to CT in detecting bone metastasis, however, it is not validated by a prospective study Besides, as SUVmax is a metabolic parameter in oncology imaging, we can serve as a reliable semiquantitative indicator to differentiate bone lesions We conducted a prospective clinical trial at Shanghai Sixth People’s Hospital Inclusion criteria were as follows: referred for diagnostic biopsy on a suspicion of metastatic disease Exclusion criteria included contraindications for biopsy 205 patients participated in the cohort study, then were randomized into PET/CT and CT group They underwent 18F-FDG PET/CT and CT separately to confirm accurate location, then both received CT-guided bone biopsy to confirm The sensitivity, specificity and accuracy were calculated In PET/CT group, malignant bone metastases were found in 83/137 patients and biopsies proved 80 were actual metastases In CT group, 48 malignant bone metastases were spotted and 47 were truly decisive The sensitivity, specificity and accuracy of 18F-FDG PET/CT and CT are 99% vs 87%, 95% vs 93%, and 97% vs 88% A chi-square test was utilized to analyze The sensitivity of 18F-FDG PET/CT is better than CT (P=0 0065), but the specificity and accuracy had no differences, indicating 18F-FDG PET/CT could detect more bone metastatic lesions potentially than CT We also found metastasis malignant lesions had higher bone SUVmax than benign (median 9 3 vs 4 25, p &amp;lt;0 001) ROC curves were asked to evaluate the differential efficacy of SUVmax In all 137 patients, the SUVmax 6 3 showed an AUC of 0 874 to predict malignant metastases Our research shows that [18F]FDG PET/CT has greater sensitivity in detecting malignant bone metastases than CT, and SUVmax can be different criteria for determining the malignancy of bone lesions Citation Format: Hui Zhao, Yujie Chang, Zhiyuan Jiang, Zhiyu Wang, Shunyi Ruan. 18F-FDG PET/CT detects potentially malignant bone metastases in patients with suspected lesions: A prospective clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT543.
Abstract 2818: Targeting solid tumors with GDT002, a first-in-class γδTCR-based T cell therapy
Authors: Esther Drent, Andrea Bisso, Sjoerd Baardman, Dagmar Verweij, Estefania Salcedo, Chris Coomans, Steven Braem, Sander van de Weg, Sara Melief, Haakan Norell, Marleen van Loenen, Stefania Gobessi, Mark Throsby
Journal: Cancer Research (2022)

Abstract Broad application of cell therapies like CAR-T have been hampered by a lack of tumor-specific targets. Gadeta leverages the natural HLA-independent tumor recognition capabilities of γδTCRs combined with the proliferative capacity and robust tumor killing of αβT cells to develop tumor-specific cell therapies. γδT cells expressing Vγ9Vδ2 TCRs are the most common subtype found in peripheral blood. They sense the presence of phosphoantigens (pAgs) upregulated in malignant cells due to a dysregulated mevalonate pathway. The Vγ9Vδ2 TCR expressed by GDT002 was isolated from a PBMC-derived γδT cell of a healthy donor and was selected for its broad and strong tumor reactivity. GDT002 is currently being evaluated in a multicenter first-in-human phase 1/2 study for the treatment of Multiple Myeloma (NCT04688853). Here we describe studies carried out to identify potential solid tumor indications which could be effectively targeted by GDT002. Tumor reactivity was tested against cell lines from different cancer types in the presence of pamidronate, a clinically approved N-bisphosphonate that boosts pAgs levels. Significant GDT002 reactivity, in terms of cytotoxicity and cytokine release, was observed against most tumor targets. In a more complex ex vivo 3D co-culture system, GDT002 reactivity was also observed towards a broad panel of patient-derived tumor organoids. In contrast, there was no or very limited GDT002 reactivity against primary healthy cells. From our broad screening of solid tumor types, we identified ovarian cancer as a promising indication for GDT002. GDT002 displayed significant reactivity towards 4/5 ovarian cell lines and 9/10 patient-derived ovarian cancer organoids in the presence of pamidronate. To study GDT002 in vivo, we investigated the biodistribution of i.v. administered pamidronate. In tumor-bearing mice, intra-tumor pamidronate concentrations were detected during the 7-day observation period, allowing targeting by GDT002. Taken together, our results demonstrate that GDT002 has a potent anti-tumor activity across a broad spectrum of solid and liquid tumor types. We have identified ovarian cancer as a potential indication to explore the clinical effect of GDT002 against solid tumors. Citation Format: Esther Drent, Andrea Bisso, Sjoerd Baardman, Dagmar Verweij, Estefania Salcedo, Chris Coomans, Steven Braem, Sander van de Weg, Sara Melief, Haakan Norell, Marleen van Loenen, Stefania Gobessi, Mark Throsby. Targeting solid tumors with GDT002, a first-in-class γδTCR-based T cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2818.
Abstract 3206: Three-dimensional tumor angiogenesis mapping in metastatic gastric cancer patients
Authors: Jihoon Ko, Sujin Hyung, Minae An, Noo Li Jeon, Jeeyun Lee
Journal: Cancer Research (2022)

Abstract Background: Patients with gastric cancer (GC) develop malignant ascites as the disease progresses due to peritoneal metastasis. The presence of malignant ascites is a critical prognostic sign of tumor progression. With an understanding of these patient subsets, better optimized treatment strategies are needed. Method: We analyzed whole exome and transcriptome sequences of ascites or primary tumor samples obtained from 46 patients with advanced gastric cancer. In addition, we engineered a microfluidic-based gastric cancer patient-on-a-chip (GRASP) to develop a tumor-induced patient-specific angiogenesis model and evaluate the ramucirumab responses. Results: Through single-cell sequencing, 46 patients were classified into two groups according to the level of KDR gene (VEGFR2) expression. (high KDR, N=25; low KDR, N=21) In the group with high VEGFR2 expression, 68% (17 of 25) samples were from ascites, and all samples with low KDR were from primary tumors. In the GRASP system, the quantitative results of random co-culture of PDCs from 46 patients with blood vessels demonstrated high concordances to the sequence results. In addition, the angiogenesis inhibitory effect of Ramucirumab was also high in the KDR high group. Conclusion: Understanding angiogenesis inhibition as part of a therapeutic strategy considering tumor microenvironment has important clinical implications. It would be a significant outcome for our analysis system to bring therapeutic benefits to GC patients. Citation Format: Jihoon Ko, Sujin Hyung, Minae An, Noo Li Jeon, Jeeyun Lee. Three-dimensional tumor angiogenesis mapping in metastatic gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3206.
Abstract 3952: A novel Mcl-1 inhibitor induces cells death in a caspase-dependent manner and increases the efficacies of Venetoclax and ABT-737 in multiple myeloma cells
Authors: Omar S. Al-Odat, Rahul S. Tripathi, Sandeep K. Srivastava, Krishne Gowda, Shantu G. Amin, Tulin Budak-Alpdogan, Subash C. Jonnalagadda, Manoj K. Pandey
Journal: Cancer Research (2022)

Abstract Multiple myeloma (MM) is a deadly malignancy of the blood, characterized by the uncontrolled proliferation of plasma cells. MM is challenging to diagnose and treat, accounting for approximately 12% of hematologic malignancies. The overexpression of anti-apoptotic proteins, particularly Myeloid cell leukemia 1 (Mcl-1), play a significant role in the pathogenesis of MM. The overexpression of Mcl-1 is associated with acquired resistance and poor prognosis. Thus, inhibition of the Mcl-1 protein is an attractive therapeutic strategy against myeloma cells. We synthesized and developed a novel Mcl-1 inhibitor, KS18. The preclinical testing of this novel agent is investigated in MM cell lines. Through docking studies, we predicted that KS18 interacts with Mcl-1. KS18 down-regulates the expression of Mcl-1 in MM cells in a dose- and time-dependent manner. Suppression of Mcl-1 expression by KS18 correlated with activation of caspases, PARP- cleavage, and apoptosis. However, this molecule had no effect on the expression of Bcl-2 and Bcl-xL proteins. Importantly, KS18 markedly enhances the efficacies of Venetoclax and ABT-737 in MM cells. Our results propose that targeting Mcl-1 by KS18 may represent a new viable strategy for MM treatment. Citation Format: Omar S. Al-Odat, Rahul S. Tripathi, Sandeep K. Srivastava, Krishne Gowda, Shantu G. Amin, Tulin Budak-Alpdogan, Subash C. Jonnalagadda, Manoj K. Pandey. A novel Mcl-1 inhibitor induces cells death in a caspase-dependent manner and increases the efficacies of Venetoclax and ABT-737 in multiple myeloma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3952.
Reply to Yuxuan Song, Caipeng Qin, and Tao Xu’s Letter to the Editor re: J. Alberto Nakauma-González, Maud Rijnders, Job van Riet, et al. Comprehensive Molecular Characterization Reveals Genomic and Transcriptomic Subtypes of Metastatic Urothelial Carcinoma. Eur Urol 2022;81:331–6
Authors: J. Alberto Nakauma-González, Maud Rijnders, Harmen J.G. van de Werken, Martijn P.J. Lolkema, Joost L. Boormans
Journal: European Urology (2022)
Abstract 2712: Establishing the early genetic progression of cancers with unobtainable premalignant disease
Authors: Ignaty Leshchiner, Edmund A. Mroz, Justin Cha, Daniel Rosebrock, Oliver Spiro, Juliana Bonilla-Velez, William Faquin, Armida Lefranc-Torres, Derrick Lin, William Michaud, Gad Getz, James W. Rocco
Journal: Cancer Research (2022)

Abstract Premalignant tissue samples collected at different timepoints along the path to invasive tumors have been used to establish the typical order of somatic genetic events in several cancer types. For many other cancer types, however, precancer tissue is unobtainable, leaving the genetic progression unknown. Here, we demonstrate an approach that can reconstruct progression histories for such cancers from exome sequencing of primary tumors. We validated our recent computational method, PhylogicNDT, on classic, HPV-negative head and neck squamous cell carcinoma (HNSCC), recapitulating the previous experimentally determined sequence of genetic events that occur during progression. We uncovered progression of HPV-positive HNSCC tumors, which lack premalignant tissue, identifying subtype specific early drivers. We associated the timing of major changes in ploidy with the development of intra-tumor genetic heterogeneity and shorter overall survival. In cancers with unobtainable premalignant tissue, our approach can fill the knowledge gap about early progression, providing the basis for development of experimental models and methods for early detection, interception, and prognostication. Citation Format: Ignaty Leshchiner, Edmund A. Mroz, Justin Cha, Daniel Rosebrock, Oliver Spiro, Juliana Bonilla-Velez, William Faquin, Armida Lefranc-Torres, Derrick Lin, William Michaud, Gad Getz, James W. Rocco. Establishing the early genetic progression of cancers with unobtainable premalignant disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2712.
Abstract 59: Optimization of high-throughput, high-depth, targeted single-cell DNA sequencing to pancreatic ductal adenocarcinoma
Authors: Haochen Zhang, Elias-Ramzey Karnoub, Ronan Chaligné, Ignas Masilionis, Alvin Makohon-Moore, Jungeui Hong, Christine Iacobuzio-Donahue
Journal: Cancer Research (2022)

Abstract Purpose of study: Despite insights gained by bulk DNA sequencing of cancer it remains challenging to resolve “mixed signals”, i.e. the admixture of normal and tumor cells, and/or of distinct tumor subclones. Bulk sequencing of pancreatic ductal adenocarcinoma (PDAC) has been particularly problematic due to the high stromal content and resulting low tumor cellularity. Strategies to account for this have included laser capture microdissection yet this is a laborious process not amenable to high-throughput pipelines. We sought to develop and apply a high-throughput, high-depth, targeted single-cell DNA sequencing (scDNA-seq) method to account for these issues, including the ability to extract high quality genomic information from low purity and archival samples. Experimental procedures: Bulk whole exome sequencing (WES) was performed on 29 biologically distinct samples. For single cell sequencing, we developed a custom panel containing 186 amplicons covering 93 genes that represent the most common germline and somatic targets reported in PDAC. Based on a commercially available system that enables automatic enzymatic and mechanical tissue disruption with integrated fluidic processes, we optimized a nuclei extraction workflow from frozen tissues that is highly compatible with downstream microdroplet-based single-cell encapsulation and library preparation. With it we generated scDNA-seq data from archival tissues of 15 PDAC patients at varying stages of the disease. Results were compared to that found in matched bulk sequencing data. Summary of new, unpublished data and conclusions: 42 samples were analyzed by single cell sequencing. Our nuclei extraction workflow generated on average 2867 single cell libraries per sample at &amp;gt;80X read depth. The single-cell results aligned well with matched bulk data in terms of the detection of key genetic variants and their variant allele frequency (VAF). We also identified additional driver variants not seen by WES, some with direct clinical evidence. Benefits of this workflow over preexisting methods are its speed of sample preparation, efficiency of sample use (particularly for small samples), flexibility by allowing for storage of excess extracted nuclei, and economy of scale. Together, these features support preparation of large numbers of cancer samples in a relatively short period of time. Citation Format: Haochen Zhang, Elias-Ramzey Karnoub, Ronan Chaligné, Ignas Masilionis, Alvin Makohon-Moore, Jungeui Hong, Christine Iacobuzio-Donahue. Optimization of high-throughput, high-depth, targeted single-cell DNA sequencing to pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 59.
Abstract 5758: Characteristic profile of blood-based ctDNA suggests angiogenesis and immune escape in hepatocellular carcinoma
Authors: Lin Chia Yan, Liu Miao, Hu Xue, Huang Meng Li
Journal: Cancer Research (2022)

Abstract Background: Circulating tumor DNA (ctDNA) is a type of DNA released from tumor cells captured in blood circulation system. It provides a noninvasive approach to interrogate a patient’s genomic landscape and actionable mutations with well application prospect. However, the difference of genomic profiles between tissue and ctDNA still brings confusions to related researches. Therefore, we tried to elucidate whether blood-based ctDNA has its own characteristic profile to reflect tumor status in hepatocellular carcinoma (HCC). Methods: Tumor tissue and blood samples from 118 HCC patients of Xiangya Hospital Central South University, were analyzed using NGS (panel on 147 gene). NGS data from a Chinese population extended cohort (385 tissues and 79 blood samples) of HCC were used to validate the mutation characteristics. Data from HCC cohorts of The Cancer Genome Atlas (TCGA) was used to analyze the disease-free survival (DFS) of different mutations. Results: In the hospital cohort, there were 9 high-frequency mutant genes in tissue and blood, including TP53 (74.58% vs 74.58%), MSH2(23.73% vs 8.47%), LRP1B (20.34% vs 23.73%), ATM (18.64% vs 13.56%), CTNNB1 (11.86% vs 13.56%) et.al which consistent with previous reports. There were 32 genes (74.04%) with a mutation frequency of more than 6% that were unique to blood samples. In extended cohort, the mutation profile was similar to the hospital cohort, in which 35 genes (52.24%) specific in ctDNA profile and 18 genes of them identical to the hospital cohort. Interestingly, when these ctDNA-specific genes were analysed by gene ontology, most genes were involved in angiogenesis. The prognostic analysis in ctDNA-specific genes showed that patients with higher level of MAP3K1 had worse DFS (p=0.028). In addition, the gene co-expression network analysis showed MAP3K1 and NOTCH1/2/3 expression had a significant positive correlation, that Notch family members were also belonged to the ctDNA-specific genes and associated with tumor immune escape. Conclusions: The results showed the mutation characteristic of tissues and ctDNA in HCC, and suggest that angiogenic and tumor immune escape related ctDNA-specific genes might be able to predict recurrence risk independently of baseline tissue samples. Citation Format: Lin Chia Yan, Liu Miao, Hu Xue, Huang Meng Li. Characteristic profile of blood-based ctDNA suggests angiogenesis and immune escape in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5758.
Abstract LB567: Dramatic in vivo efficacy of the EZH2-inhibitor tazemetostat in PBRM1-mutated human chordoma xenograft
Authors: Thibault Passeri, Ahmed Dahmani, Julien Masliah-Planchon, Adnan Naguez, Marine Michou, Rania El-Botty, Sophie Vacher, Rachida Bouarich, André Nicolas, Marc Polivka, Coralie Franck, Anne Schnitzler, Fariba Némati, Sergio Roman-Roman, Franck Bourdeaut, Homa Adle-Biassette, Hamid Mammar, Sébastien Froelich, Ivan Bièche, Didier Decaudin
Journal: Cancer Research (2022)

Abstract Background: Chordomas are considered as rare bone neoplasms characterized by a high level of recurrence and a poor long-term prognosis. Considering their chemo-radio-resistance, alternative treatment strategies are therefore strongly requested, but their development is limited by the paucity of relevant preclinical models. Mutations affecting genes of the SWI/SNF complex including PBMR1 are frequently found in chordomas, suggesting a potential therapeutic effect of epigenetic regulators in this indication. Methods: Thirty-eight chordoma specimens derived from primary patients’ tumors were grafted into nude mice. Relationship between grafted tumors and clinical, biological and therapeutic features of corresponding patients were investigated. We subjected the established PDX models to histopathological and genetic examination; finally, a therapeutic program focused on the EZH2-inhibition was performed in one PDX model. Results: Twelve PDX models were established and characterized on histological and biomolecular features. Patients whose tumors were able to grow into mice had a statistically significant lower progression-free survival than those whose tumors did not grow after in vivo transplantation (p=0.007). All PDXs maintained the same histopathological features as patients’ tumors. Homozygous deletions of CDKN2A/2B (58.3%) and PBRM1 (25%) variants were the most common genomic alterations found. In the tazemetostat treated PDX model harboring a PBRM1 variant, an overall survival of 100% was observed. Conclusion: Our panel of chordoma PDXs represents a useful preclinical tool for both pharmacologic and biological assessments. The first demonstration of a high antitumor activity of tazemetostat in a PDX model harboring a PBRM1variant supports further evaluation of EZH2-inhibitors in this subgroup of chordomas. Citation Format: Thibault Passeri, Ahmed Dahmani, Julien Masliah-Planchon, Adnan Naguez, Marine Michou, Rania El-Botty, Sophie Vacher, Rachida Bouarich, André Nicolas, Marc Polivka, Coralie Franck, Anne Schnitzler, Fariba Némati, Sergio Roman-Roman, Franck Bourdeaut, Homa Adle-Biassette, Hamid Mammar, Sébastien Froelich, Ivan Bièche, Didier Decaudin. Dramatic in vivo efficacy of the EZH2-inhibitor tazemetostat in PBRM1-mutated human chordoma xenograft [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB567.